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Abstract

Aim: Secondary central nervous system (CNS) involvement is a devastating and usually fatal complication of non-Hodgkin’s lymphoma (NHL). We aimed to evaluate the incidence of secondary CNS involvement and the value of 18F-FDG PET/computed tomography (CT) imaging in the detection of secondary CNS involvement in patients with NHL.

Methods: A total of 123 immunocompetent patients (58 men, 65 women; mean age: 56.5±19.2) with biopsy-proven NHL who underwent 18F-FDG PET/CT for primary staging (n=68) and restaging (n=55) of recurrent disease were reviewed retrospectively. Those with secondary CNS involvement as diagnosed on PET/CT were identified. CNS involvement was confirmed by MRI and cerebrospinal fluid cytology.

Results: The clinical Ann Arbor stages of the patient population were as follows: stage I – 10 patients; stage II – 44 patients; stage III – 32 patients, and stage IV – 37 patients. PET/CT detected CNS involvement in six patients. The ages of patients with CNS disease ranged from 23 to 68 (mean: 47.2) years. Three patients presented with CNS involvement associated with systemic disease manifestation at initial diagnosis; one patient had isolated CNS relapse and two had relapsed systemic NHL with progression to CNS involvement. Relapse interval was 8–12 months following initial diagnosis. The types of CNS involvement in patients were as follows: parenchymal (n=2), leptomeningeal (n=2), both parenchymal and leptomeningeal (n=1), and pituitary gland involvement (n=1), which is an uncommon manifestation. Median duration of survival was 2.5 months after the diagnosis of CNS involvement.

Conclusion: The incidence of secondary CNS involvement was 4.4% at initial diagnosis and 5.4% among patients with relapse of lymphoma in our study. PET/CT is a sensitive, objective, and valuable method for the diagnosis of secondary CNS involvement in patients with NHL. In addition, pituitary gland involvement, as a very rare manifestation of secondary CNS lymphoma, has been shown.

Introduction

Secondary central nervous system (CNS) involvement is a serious and fatal complication of aggressive non-Hodgkin’s lymphoma (NHL) 1. The frequency of secondary CNS involvement in patients with NHL ranges from 5 to 25% and is highly dependent on histological subtypes 2. CNS relapses can manifest either as an isolated event or as part of the widespread progression of the disease. In half of the cases with CNS relapse, there is an additional systemic relapse 3. Even though leptomeningeal involvement is more frequent than parenchymal disease, both brain parenchyma and the leptomeningeal compartment may be involved 1,3. However, pituitary gland involvement is an uncommon finding 4.

Lymphoma with secondary CNS involvement has an extremely poor prognosis, necessitating immediate diagnosis and additional treatment strategies. As data on secondary CNS lymphoma are limited, an efficient therapeutic modality has not been established yet 5. In contrast, treatment approaches are well established and therapeutic results are much better for patients with primary CNS lymphoma. Therefore, differential diagnosis of secondary CNS involvement from primary CNS lymphoma is essential not only to guide the therapeutic approach but also for prognostication and assessment of therapy response on follow-up.

The value of 18F-FDG PET/computed tomography (CT) in staging and restaging of patients with NHL, as well as in treatment response evaluation, has been well documented. Moreover, on the basis of the metabolic information derived from PET/CT, individualization of treatment may be possible in clinical practice. However, in the literature, there are still limited data on the use of PET/CT for the detection of secondary CNS involvement in NHL. In this report, we aimed to evaluate the incidence of secondary CNS involvement in patients undergoing 18F-FDG PET/CT at our center and define the value of PET/CT imaging in the detection of secondary CNS involvement of NHL by presenting cases with different patterns of CNS involvement, including pituitary gland infiltration. In addition, we aimed to evaluate the clinical characteristics and outcome of patients with secondary CNS involvement of NHL as detected by PET/CT at our center.

Methods

All patients with biopsy-proven NHL who underwent 18F-FDG PET/CT at our institution (n=123 patients, 58 men, 65 women) from January 2009 to April 2012 were enrolled into this retrospective study. PET/CT was indicated for initial staging in 68 patients and for restaging of recurrent disease in 55 patients. The classification of NHL was performed on the basis of the 4th edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues published in 2008 6. This study was approved by the ethics committee of our institution.

PET/CT imaging was performed using an integrated PET/CT scanner (Siemens Biograph 6 – True Point PET/CT systems; Siemens, Chicago, Illinois, USA). Patients were asked to fast for at least 6 h before being injected with 5.3 MBq/kg (144 µCi/kg) of 18F-FDG. The blood glucose levels were less than 150 mg/dl in all patients at the time of the 18F-FDG injection. Unenhanced CT images were acquired for attenuation correction from the skull vertex to mid-thigh using 3 mm slice thickness and calculated effective mAs on the basis of patient weight. The PET and CT images were reviewed on a workstation (Leonardo; Siemens Medical Solutions, Erlangen, Germany) in all standard planes along with maximum intensity projection images and were analyzed visually and quantitatively by two reviewers experienced in interpreting PET/CT scans. Findings were recorded by consensus.

In this study, leptomeningeal and parenchymal involvements were considered as CNS involvement. Parenchymal involvement was diagnosed when a mass lesion was detected in the brain on PET/CT and confirmed by MRI and cerebrospinal fluid (CSF) cytology. Leptomeningeal involvement was confirmed when malignant cells were detected in the CSF cytological study conducted after PET/CT.

MRI for the brain and spine was not routinely performed for all patients. However, patients with pathological findings on 18F-FDG PET and patients with neurological symptoms underwent MRI imaging for the brain and spine when necessary.

Results

PET/CT detected nodal and/or extranodal disease in all patients. The mean age in our patient population was 56.5±19.2 (range: 6–93) years. Clinical Ann Arbor stages of the patient population were as follows: stage I – 10 patients; stage II – 44 patients; stage III – 32 patients; and stage IV – 37 patients. For all patients, PET findings were proven to be positive by histopathological verification.

The subtypes of NHL in the study population were as follows: diffuse large B-cell lymphoma (DLBCL) in 72 patients, B-cell lymphoma with features intermediate between DLBCL and Burkitt’s lymphoma in two patients, B-cell lymphoma with features intermediate between DLBCL and Hodgkin’s lymphoma in 17 patients, Burkitt’s lymphoma in two patients, follicular lymphoma in five patients, MALT lymphoma in three, mantle cell lymphoma in eight, T-cell lymphoma in three, small lymphocytic lymphoma in eight, and lymphoplasmacytic lymphoma in three patients.

In our patient population, six patients with CNS involvement were identified. Detailed clinical information on patients with CNS disease has been given in Table 1. All had DLBCL according to WHO 2008 classification. None of the patients with Burkitt’s lymphoma or B-cell lymphoma with features intermediate between DLBCL and Burkitt’s lymphoma or other NHL subtypes had CNS disease in the study group. CNS involvement was diagnosed by PET/CT and confirmed by MRI and/or CSF cytology. None of our patients had false-positive findings on 18F-FDG PET on assessment of their brain in this study.

Three patients presented with CNS involvement associated with systemic disease manifestation at initial diagnosis (4.4%); one patient had isolated CNS relapse and two had relapsed systemic NHL with progression to secondary CNS involvement (5.4%). Patients with NHL relapse had been treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, oncovin and prednisone) chemotherapy previously and patients with CNS relapse did not have a history of intrathecal prophylaxis administration. Relapse time was 8–12 months for patients with CNS relapse.

Two patients had leptomeningeal involvement (Fig. 1), two had parenchymal involvement (Fig. 2), one had both parenchymal and leptomeningeal involvement, and one patient had pituitary gland involvement. 18F-FDG uptake in the tumor was usually higher than that in the contralateral identical region, and tumors were visually detectable in 18F-FDG PET images. The average SUVmax in the tumor was 27.2±5.4 and this was about 2.5 times higher than the average SUV in the contralateral normal cortical gray matter (9.7±2.1). Corresponding to the pathological findings on PET/CT, MRI detected hyperintense lesions in the spinal cord and brain parenchyma on T2-weighted images with pathological contrast enhancement on postcontrast images.

The ages of patients with CNS involvement ranged from 23 to 68 years with a mean of 47.2 years (Table 1). None of these patients had immunodeficiency disorders. Five patients had stage IVE disease and only one patient had stage IIE disease at the time of diagnosis. All patients were seen to have extranodal involvement on PET/CT. ECOG performance status was at least 2 in all patients and the International Prognostic Index (IPI) was high in all patients with a median of 4. Similarly, age-adjusted IPI scores were 2–3 in these patients. Serum LDH levels were normal in four patients and significantly elevated in two (351 and 1035 IU/l). Median survival was 2.5 months after the diagnosis of CNS involvement.

MRI of the brain and/or the spine was not routinely performed in our patient population. However, two patients who had neurological symptoms (ataxia, which was proven to originate from the vestibular system in one patient and from peripheral neuropathy in another) underwent MRI imaging of the CNS. No abnormal findings were detected on MRI, and 18F-FDG PET imaging results were normal for the brain.

In this study, among the subgroup of patients who underwent 18F-FDG PET/CT for restaging of recurrent disease, six received intrathecal prophylaxis. Two patients with Burkitt’s lymphoma and four with extranodal involvement associated with high risk for CNS relapse (testicular involvement in one patient, paranasal involvement in two, and adrenal gland involvement in one patient) received intrathecal methotrexate. None of our patients with CNS relapse had CNS prophylaxis.

Discussion

Secondary CNS involvement is a devastating complication of aggressive NHL. The incidence of CNS relapse in lymphoma patients varies greatly among different NHL subtypes. Following primary CNS lymphoma and primary ocular lymphoma, patients with lymphoblastic lymphoma and Burkitt’s lymphoma are at higher risk of developing CNS relapse compared with other lymphoma subtypes 7. In general, the incidence of CNS relapse is regarded as ∼5% 5,8. However, many clinical factors such as advanced stage, age over 60 years, bone marrow involvement, extranodal involvement, elevated lactate dehydrogenase levels, and poor performance status have been identified as risk factors for CNS involvement in NHL 1,9,10. In this study, similar to the historical data, we observed that 4.4% of patients with NHL presented with secondary CNS involvement at the time of diagnosis, and 5.4% of patients developed CNS relapse or progression to CNS. In our patient group, all patients with secondary CNS involvement had other sites of extranodular disease as a predisposing factor for CNS involvement of NHL. In addition, advanced stage of disease and high IPI scores were the most common predisposing factors following the presence of extranodular disease.

Accurate diagnosis of secondary CNS involvement in NHL is essential. The standard method is microscopic examination of samples for the presence of malignant cells. In general, CSF cytology is regarded as the gold standard for diagnosis 7. More recently, the diagnostic sensitivity of flow cytometry was found to be higher than that of cytomorphology, and the National Comprehensive Cancer Network (NCCN) 11 recommended the use of flow cytometry for the diagnosis of CNS lymphoma. However, recommendations for CSF examinations by lumbar puncture are generally limited to certain NHL subtypes or to certain conditions in which the patient has high-risk factors associated with CNS involvement 11.

There are conflicting results on the most common manifestations of CNS disease in patients with relapsed NHL. According to previous reports, unlike primary CNS lymphomas, secondary CNS lymphomas present as leptomeningeal metastases in two-thirds of patients and as parenchymal metastases in one-third of them 12. However, recent reports indicate that secondary CNS involvement manifests as parenchymal disease in 60% of patients with DLBCL 13. Lymphoma involving the pituitary gland is an exceedingly infrequent event 4,14,15. In this study, parenchymal involvement was more frequent than leptomeningeal disease, and pituitary gland involvement was detected in one patient. Even though the incidence of secondary CNS involvement of NHL as evidenced by 18F-FDG PET/CT in this study was found to correlate with historical data, possible underestimation of occult leptomeningeal and or parenchymal disease on 18F-FDG PET is subject to debate. Having the advantage of highest soft tissue resolution, gadolinium-enhanced MRI would be the modality of choice for CNS imaging. However, current literature lacks evidence derived from such a comparison in assessing the CNS of NHL patients, as cranial and spine MRI studies are not routinely performed for all patients with NLH in clinical practice. Similarly, a comparison between 18F-FDG PET and MRI was not possible in our study because MRI of the CNS was only limited to patients with neurological symptoms and to those with pathological 18F-FDG uptake in CNS.

In general, secondary CNS involvement tends to occur at a median of 5–12 months after the diagnosis of NHL 12,16. In half of the patients, CNS involvement is associated with systemic relapse, and CNS disease generally occurs as an early manifestation of relapsed lymphoma. Either isolated or in the context of systemic relapsed disease, the prognosis of CNS recurrence is poor with a median survival of 2–6.5 months 16,17. In this study, time to relapse with CNS involvement was 8–12 months and two-thirds of patients with CNS relapse had systemic disease manifestation as well. Similar to historical data, we observed that median survival time after relapse with CNS involvement was 2.5 months.

When CNS relapse occurs as a part of systemic disease manifestation or during disease progression, it often indicates an end-stage disease with resistance to most therapeutic strategies 2,8,9. In contrast, isolated CNS disease with no evidence of systemic involvement may be potentially treatable when combined systemic and intraventricular chemotherapy is administered along with radiation therapy 5,8,9,17. Compared with primary CNS lymphoma and isolated CNS relapse of systemic lymphoma, secondary CNS lymphoma has an even worse prognosis, with a median survival of only months and very few reported long-term survivors 19. Distinguishing secondary CNS lymphoma from primary CNS lymphoma is essential not only to define a therapeutic approach but also to assess therapy response on follow-up. For both of these groups of patients, there has been interest in defining patients with high risk for CNS relapse.

Several studies have been conducted to discriminate patients who may benefit from CNS prophylaxis. This is a fundamental, yet open, issue. The routine use of intrathecal CNS prophylaxis is well described in patients with Burkitt’s and lymphoblastic lymphomas, whereas subsequent need for prophylaxis is less well described in patients with DLBCL 9. The effectiveness of intrathecal prophylaxis and the combination of high-dose systemic methotrexate and intrathecal chemotherapy are controversial issues 15,18,20–23. Current literature agrees on the need for further investigations to better identify patients who are at high risk and to protect them from potential complications associated with such aggressive administrations 8.

The discrimination between isolated CNS relapse and CNS involvement with systemic disease progression may have significant value for guiding therapy. In addition, differential diagnosis of primary CNS lymphoma and secondary CNS lymphoma or systemic spread of primary CNS lymphoma is crucial not only to define a therapeutic approach but also to assess therapy response on follow-up 24. To this end, differential diagnosis must be made as rapidly as possible to allow the early institution of effective therapy.

The use of 18F-FDG PET/CT in the management of patients with NHL has become essential for initial staging and restaging. The superiority of 18F-FDG PET over CT for assessment of extranodal involvement is, today, well established 25. In addition, the impact of 18F-FDG PET/CT has been well recognized for evaluation of therapy response in NHL. Several reports have emphasized the impact of pretreatment 18F-FDG PET and early 18F-FDG PET imaging after one or two cycles of induction chemotherapy 26,27. Furthermore, PET has been integrated into the revised response criteria for malignant lymphoma 28.

Similar to its role in systemic lymphoma, the use of 18F-FDG PET/CT in the pretreatment setting of patients with primary CNS lymphoma is also well established 29. In addition, recent studies have evaluated the prognostic value of 18F-FDG PET/CT in primary CNS lymphoma and authors have found that pretreatment 18F-FDG uptake may have a prognostic value in newly diagnosed primary CNS lymphoma 30. However, current literature lacks sufficient data on the use of 18F-FDG PET in CNS relapse of lymphoma. In contrast to clinical studies on systemic lymphoma and primary CNS lymphoma, the rarity of secondary CNS lymphoma makes prospective studies of this entity difficult to perform. Reports on the use of 18F-FDG PET to detect CNS involvement in NHL are limited to a few case studies. There are no large case series or prospective trials on this rare and fatal complication of lymphomas. In addition, there are no studies that evaluate the prognostic performance of 18F-FDG PET/CT in CNS involvement of lymphoma in comparison with CSF cytology. Although retrospective, our study demonstrates the incidence of CNS involvement in a group of patients with aggressive NHL who underwent 18F-FDG PET/CT and allows us to assemble the largest series to date of patients with CNS involvement as detected on PET/CT.

However, there are some limitations to this study because of its retrospective nature. First, there may have been clinical bias in referring patients for a PET/CT scan. Second, because lumbar puncture is not a routine procedure, it was not performed in all cases; hence, results of a real comparison between CSF cytology and PET/CT findings are not available for most patients. For this reason, the question whether subclinical or microscopic CNS involvement might have been underdiagnosed on PET/CT remains unclarified and is still subject to further research. To this end, although comparable to historical data, the results of this study should not be considered as the real incidence of CNS involvement in patients with NHL.

To our knowledge, this is the first study to demonstrate the incidence of CNS disease detected by PET/CT in patients with NHL and to emphasize the value of 18F-FDG PET/CT in the detection of CNS involvement. Further, although response evaluation and prognostication cannot be justified by a single case, the pretreatment and post-treatment 18F-FDG images of case no. 2 may highlight the value of 18F-FDG PET/CT in the evaluation of response to cranial radiation therapy. In addition, this study demonstrates the pituitary gland involvement detected on PET/CT as a very rare site of CNS involvement in patients with NHL (Fig. 3).

Conclusion

CNS dissemination is a rare but usually fatal complication of aggressive lymphomas. Prophylaxis modalities to prevent CNS dissemination in aggressive lymphomas cannot be widely applied to every lymphoma patient as they are associated with increased risk for neurotoxicity. Therefore, early identification of patients with CNS involvement is crucial in the management of these malignancies. Whole-body PET/CT, starting from the vertex, should be used in the case of patients with aggressive high-grade lymphomas for accurate initial staging and restaging. PET/CT is a sensitive and valuable method for the detection of CNS involvement in patients with NHL. Further, we believe that improved metabolic imaging with PET will presumably play an important role in the planning of new targeted therapies and for prognostication in the future.

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